Two principal Immunopathogenetic features characterize the autoimmune inflammatory myopathies, polymyositis, dermatomyositis, and related diseases: lymphocytic destruction of muscle cells, and humoral autoimmunity distinguished by a striking set of disease-specific autoantibodies. Although the muscle cell destruction is mediated by lymphocytes, the autoantibodies, particularly those directed against the family of functionally related but structurally diverse aminoacyl-tRNA synthetases, seem to offer a useful window on the disease and have been the focus of much of this group's research for a number of years. Work continues, although at a diminished intensity, on the humoral autoimmunity. The goal of these studies is to design better ways to treat myositis Recently our attention has focused on the lymphocytic destruction and the death of myocytes. The tissue damage, in contrast to the majority of autoimmune tissue damage, is associated with a predominantly CD-8+ infiltrate. Furthermore, muscle is one of the few tissues in which MHC Class I is constitutively absent, but in myositis, it is markedly up-regulated on myocytes, raising the possibility that this up-regulation plays a role in initiating and sustaining the inflammation. The following areas have been pursued this year: 1) Studies of the synthesis of cytokines, immune co-stimulatory molecules, and MHC by myocytes in response to inflammatory stimuli have shown that muscles cells both respond to and can synthesize MHC molecules, co-stimulatory molecules, and cytokines in response to inflammatory stimuli, thereby establishing a much more active role for muscle in controlling immune attack. 2) The apparent absence of apoptosis in biopsies from patients with immune destruction of muscles in myositis has stimulated us to study the apoptosis of muscle cells in culture, both at NIH and in collaboration with a group at Johns Hopkins. 3) Transgenic mice in which MHC Class I is constitutively up-regulated or is up-regulated in skeletal muscle only, or can be up or down-regulated by the feeding of tetracycline have been made or are currently being bred to determine whether MHC up-regulation incites inflammation as it has done in several other systems. 4) The effect of methimazole, an anti-thyroid drug which down-regulated Class I in rodents, is being studied on cultured human muscle cells and on Class I of muscle and lymphocytes in patients receiving the drug in a therapeutic trial (see Z01 AR 41076-08 ARB). 5) Currently, the only project related to the autoantibodies is an attempt to obtain stable crystals of the principal autoantigenic target, histidyl-tRNA synthetase. Crystals of a truncated recombinant lacking the amino terminal coiled-coil appear to be more stable and are now being studied by Dr. Craig Hyde.